Diabetes refers to a disease process which stems from a number of causal factors and is evident from increased plasma glucose levels or hyperglycemia during the fasting state or following the administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with an increased and premature morbidity and mortality. An abnormal glucose homeostasis is often associated both directly and indirectly with changes in the lipid, lipoprotein and apolipoprotein metabolism and with other metabolic and hemodynamic diseases. Consequently, for patients with type 2 diabetes mellitus, there is a particularly high risk of macrovascular and microvascular complications, including coronary heart disease, apoplexy, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. The therapeutic control of glucose homeostasis, lipid metabolism and hypertension is of decisive importance for the clinical handling and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes or insulin-dependent diabetes mellitus (IDDM), the patients produce little or no insulin, a hormone which controls the glucose utilization. In type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM), the patients often have plasma insulin levels which correspond to or are even higher than those of non-diabetic patients. However, these patients have developed a resistance to the insulin-stimulating effect on the glucose and lipid metabolism in the large insulin-sensitive tissues, which are muscle, liver and fatty tissue, and the plasma insulin levels, although increased, are insufficient for overcoming the marked insulin resistance.
Insulin resistance is not primarily the result of a reduced number of insulin receptors, but the result of a post insulin receptor binding defect which has still not been explained. This resistance to insulin sensitivity leads to inadequate insulin activation of the glucose absorption, oxidation and storage in the muscle and to inadequate insulin suppression of lipolysis in fatty tissue and the production and secretion of glucose in the liver.
It has been found that there are a large number of compound classes which can be used for the treatment of diabetes. Those worthy of particular mention here are the inhibitors of the dipeptidylpeptidase-IV enzyme (“DP-IV inhibitors”) which are suitable for the treatment or prevention of diseases in which the dipeptidylpeptidase-IV enzyme is involved, such as e.g. diabetes and in particular type 2 diabetes.
WO 03/004498 A1 proposes as such DP-IV inhibitors substances with a pyrazine structure, among which 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine (INN: Sitagliptin) is also mentioned. In particular, a sitagliptin hydrochloride is also described. This hydrochloride is hygroscopic.
In WO 2005/003135 describes a sitagliptin dihydrogenphosphate salt which has evidently been obtained as hydrate but is phase-unstable at temperatures above 40° C. This implies that the production of relatively large amounts on an industrial scale leads to a drying process that is difficult to control.
WO 2005/072530 A1 discloses further salts of sitagliptin. These compounds too are said to be used as DP-IV inhibitors for treating diabetes. Neither WO 03/004498 A1 nor WO 2005/072530 A1 discloses compounds comprising sitagliptin and fumaric acid.
Kim et al., J. Med. Chem. 2005, 48, 141-151 have investigated orally active DP-IV inhibitors for treating type 2 diabetes. Inter alia, sitagliptin is reacted with fumaric acid for an in vivo investigation. In this process, a solid is obtained in which the ratio of sitagliptin to fumaric acid is 1:0.5. A characterization takes place only by means of NMR and HRMS. It is not stated whether the resulting solid is crystalline.
In the prior art, there is the need to provide compounds comprising sitagliptin which allow improved administration. In particular, the aim is to provide an administration form of sitagliptin which takes into consideration the requirements of the pharmacokinetics of the active ingredient and moreover can be used in the formulation of an oral administration form. In particular, the aim is to provide a compound which has an optimized low water absorption upon storage.